DK171478B1 - Process for the preparation of (S) -alpha-cyano-3-phenoxybenzyl alcohol - Google Patents

Description

The invention relates to a process for the preparation of (S) -α-cyano-3-phenoxybenzyl alcohol.

This is an intermediate product for the manufacture of esters between (S) -α-cyano-3-phenoxybenzyl alcohol and 1R, cis-2,2-dimethyl-3- (2 ', 2'-dibromovinyl) -cyclopropane-1-carboxylic acid.

The process according to the invention is characterized by the characterizing part of claim 1.

One already knows (R, S) -α-cyano-3-phenoxybenzyl alcohol, which is a racemic substance. However, no publication of (S) -α-cyano-3-phenoxybenzyl alcohol or the preparation thereof has existed so far.

Admittedly, methods are known for the cleavage of alcohols with asymmetric carbon atoms.

For example, it is known to cleave certain racemic (RS) alcohols by combining them with an optically active organic acid and, by appropriate physical treatment, separating the ester of (S) alcohol from the ester of (R) alcohol, upon which hydrolyzes these two esters to give the alcohols with (R) structure and with (S) structure.

These known methods for cleavage of the alcohols comprise, as an intermediate stage, the formation of esters. In the final step of cleavage, it is necessary to hydrolyze these esters to obtain the desired cleaved alcohol. In the case of α-cyan-3-phenoxybenzyl alcohol, it has been found that when the hydrolysis of the esters of this alcohol is carried out in an acidic or alkaline environment, the desired decomposed alcohol is not obtained but the decomposition products thereof, especially 3-phenoxybenzoaldehyde and 2-hydroxy-2- (3-phenoxy) phenylacetic acid.

Thus, no process has so far existed for a cleavage which allows (S) -α-cyano-3-phenoxybenzyl alcohol to be obtained.

The present invention provides a process for the preparation of (S) -α-cyano-3-phenoxybenzyl alcohol, and an important feature of this process is the preparation of an optically active ether as an intermediate, namely (1R, 5S) -6 , 6-dimethyl-4- (R) - ((S) -cyano (3-phenoxyphenyl) methoxy) -3-oxa-bicyclo (3.1.0.) hexan-2-one. Unlike the esters which are used in a classic manner to decompose the alcohols, this ether possesses a structure which facilitates its hydrolysis in an acidic environment, which makes it possible to obtain the desired alcohol. In addition, a good yield is obtained.

DK 171478 B1 2

It has been found that this alcohol with (S) configuration has a negative turning ability. Thus, this turning power, measured in benzene at a concentration in the vicinity of 0.8%, is of the order of -16.5 ° ± 1.5 °.

In the process of the invention, (S) -α-cyano-3-phenoxybenzyl alcohol is obtained in a practically pure state or also in a pure state and in particular (S) -α-cyano-3-phenoxybenzyl alcohol with a rotational power, measured in benzene at a concentration of ca. 0.8%, of approx. -16.5 '.

The acidic agent in which the alcohol and lactone compound is reacted are selected especially from p-toluenesulfonic acid, methanesulfonic acid, perchloric acid, m-nitrobenzenesulfonic acid, 5-sulfosalicylic acid and camphosulfonic acid.

(1R, 5S) -6,6-dimethyl-4- (R) - ((S) -cyan- (3-phenoxyphenyl) -methoxy) -3-oxa-bicyclo (3.1.0.) Hexane-2 one can be separated from its isomer, (1R, 5S) -6,6-dimethyl-4- (R) - ((R) -cyan- (3-phenoxyphenyl) methoxy) -3-oxa-bicyclo ( 3.1.0.) Hexan-2-one, by crystallization of a solvent or by chromatography.

This separation can be particularly conveniently carried out by chromatography on silica gel column.

As an acid to carry out the hydrolysis at the end of (1R, 5S) -6,6-dimethyl-4- (R) - ((S) -cyan- (3'-phenoxy-phenyl) -methoxy) -3-oxa -bicyclo (3.1.0.) hexan-2-one can advantageously be used p-toluenesulfonic acid.

Purification of the alcohol by chromatography on silica gel and elution with a mixture of benzene and ethyl acetate (9: 1) gives (S) -α-cyano-3-phenoxybenzyl alcohol with = -16.5 ° ± 1.5 ° (c = 0.8%, benzene).

(S) -α-Cyan-3-phenoxybenzyl alcohol is an industrially very useful substance. In the field of pyrethrinoid compounds, it is known that the cyclopropanecarboxylic acid esters of (S) -ix-cyano-3-phenoxy-benzyl alcohol generally have an insecticidal effect much higher than that of the corresponding esters of the (R) alcohol.

(S) -α-Cyan-3-phenoxybenzyl alcohol allows, for example, by simple esterification as set forth below in the experimental section to prepare the ester thereof with 1R.cis-2,2-dimethyl-3- (2 \ 2'-35 dibromovinyl) - cyclopropane-1-carboxylic acid, which compound is well known for its remarkable insecticidal activity.

DK 171478 B1 3

However, some of the esters of (S) - <x-cyan-3-phenoxybenzyl alcohol have not been able to be produced so far, since no alcohol with (S) -configuration was available. Thus, for example, it has been hitherto impossible to provide the ester between (S) -u-cyan-3-phenoxybenzyl alcohol and HD "-2-isopropyl-2-p-chlorophenylacetic acid. Thanks to the present invention, it is now easy to esterify ( S) -α-Cyan-3-phenoxybenzyl alcohol by means of "D" -2-isopropyl-2-p-chlorophenylacetic acid chloride to produce this compound which has been shown to have excellent insecticidal properties.

An example of the preparation of the ester of (S) -α-cyano-3-phenoxybenzyl alcohol with "D" -2-isopropyl-2-p-chlorophenylacetic acid is described below in the experimental section.

Finally, (S) -α-cyano-3-phenoxybenzyl alcohol according to the invention is obtained by an economically advantageous process which is completely original. Obtaining this alcohol enables the production of highly insecticidal esters for which no pathway has been known to date.

15

Through the present invention, it is possible to prepare the following auxiliaries - a mixture of (1R, 5S) -6,6-dimethyl-4- (R) - ((S) -cyan- (3'-phenoxyphenyl) methoxy) -3-oxa-bicyclo (3.1.0) hexan-2-one and (1R, 5S) -6,6-dimethyl-4- (R) - ((R) -cyan- (3'-phenoxyphenyl) ) - 20-Methoxy-3-oxa-bicyclo (3.1.0) hexan-2-one, - (1R, 5S) -6,6-dimethyl-4- (R) - ((S) -cyan-3 (-phenoxyphenyl) -methoxy) -3-oxa-bicyclo (3.1.0.) hexan-2-one, and - (1R, 5S) -6,6-dimethyl-4- (R) - ((R) - cyano- (3'-phenoxyphenyl) methoxy) -3-oxa-bicyclo (3.1.0.) hexan-2-one.

25

The following examples illustrate the process of the invention and the use of the compound prepared by the process.

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Example 1 (S) -α-Cyan-3-phenoxybenzyl alcohol Step A:

Mixture of (IR.SSH ^ e-dimethyM-fRMtSJ-cyano-fS'-phenoxyphenylO-methoxyl-S-oxa-bicyclo (3.1.0.) Hexan-2-one and (IR ^ SJ-ee-dimethyM-fRHfR1 -cyano ^ S'-phenoxyphenyl) methoxy) -3-oxa-bicyclo (3.1.0.) hexan-2-one

22.5 g of (R, S) -α-cyano-3-phenoxybenzyl alcohol, 9.46 g of lactone of cis-2,2-dimethyl-3S- (dihydroxymethyl) -cyclopropane-1R-carboxylic acid and 0.150 g of toluene sulfonic acid monohydrate, warms to 80® under a vacuum of 10 ** mm Hg and keeps the reaction mixture for 2 hours under these conditions, eliminating the formed water by distillation. Cool to 20 ° C to give 30.70 g of crude mixture of (1R, 5S) -6,6-dimethylM- (R) - ((S) -cyan- (3'-phenoxyphenyl) methoxy) -3-oxa -bicyclo (3.1.0) hexan-2-one and (1R, 5S) -6,6-dimethyl-4- (R) - ((R) -cyan-3'-phenoxyphenyl) methoxy) -3-oxa-bicyclo (3.1.0.) Hexan-2-one (containing as impurities mainly unreacted starting products) (mixture A).

15

Step B: (1R, 5S) -6,6-dimethyl-4- (R) - ((S) -cyan- (3'-phenoxyphenyl) methoxy) -3-oxa-bicyclo (3.1.0.) Hexane -2-one

Chromatograph the mixture A obtained in step A on silica gel eluting with a mixture of benzene and ethyl acetate (95: 5) to give 10.9g (1R, 5S) -6,6-dimethyl-4- ( R) - ((S) - Cyano- (3'-phenoxyphenyl) -methoxy) -3-oxa-bicyclo (3.1.0) hexan-2-one. Mp. 126 ° C, αQ = -71 ° (c = 1%, benzene).

U.V spectrum (ethanol): 25 turning point at 226 nm (e1 J = 319), turning point at 267 nm (E1 = 52), 1 1 turning point at 271 nm (E1 = 56), max at 276 nm (E1 = 60) ), turning point at 280 nm (E ^ J = 48)

Circular dichroism (dioxane): 30 Δε = -4.2 at 225 nm (max) Δε = +0.39 at 287 nm (max) N.M.R. spectrum (deuterochloroform):

Peaks at 1.18-1.23 ppm, characteristic of the hydrogen atoms in the twin methyl groups, peak 35 at 1.98-2.08 and 2.15-2.25 ppm, characteristic of the hydrogen atoms in cyclopropyl, peaks at 5.53 -5.56 ppm, characteristic of the hydrogen at the same carbon atom as the nitrile group DK 171478 B1 5 and of the hydrogen at the 4-position, peaks at 6.91-7.25 ppm, characteristic of the hydrogen atoms in the aromatic rings.

Step C: 5 (S) -α-Cyan-m-phenoxybenzyl alcohol In a mixture of 100 ml of dioxane and 50 ml of water, 10 g (1 R, 5 S) -6,6-dimethyl-4- (R) - ( SS) -cyan- (3'-phenoxyphenyl) -methoxy) -3-oxa-bicyclo (3.1.0.) Hexan-2-one prepared in Step B of Example 1 and 1 g of p-toluenesulfonic acid monohydrate and heating the reaction mixture to reflux, keep it under reflux for 23 hours, evaporate by distillation under reduced pressure to half the initial volume, add ethyl ether, stir, separate the organic phase by decantation, wash it with water, dry it, evaporate to dryness under reduced pressure, chromatograph the residue (9.5 g) on silica gel eluting with a mixture of benzene and ethyl acetate (9: 1) to obtain 6.1 g of (S) -α-cyano-m-phenoxybenzyl alcohol with ap = = -16 , 5 ° ± 1.5 ° (c = 0.8%, benzene).

N.M.R. spectrum (deuterochloroform):

Peak at 3.25 ppm, characteristic of the hydrogen in the alcohol group, peak at 5.42 ppm, characteristic of the hydrogen atom at the same carbon atom as the nitrile group.

Example 2 (Application Example)

The ester between (S) -α-cyano-3-phenoxybenzyl alcohol and "D" -2-isopropyl-2-p-chlorophenylacetic acid

Step A:

The salt between (+) - α-phenylethylamine and "L" -2-isopropyl-2-p-chlorophenylacetic acid 25 Into 4 liters of ethanol with 70% water (by volume) 250 g of D, L-2-isopropyl-2- p-chloro-phenylacetic acid, and the obtained solution is stirred and added with 140 g (+) - α-phenyl-ethylamine, observes a precipitate, heats the reaction mixture to reflux, adds alcohol with 70% water (by volume) until complete dissolution (i.e. 3.25 liters of solvent), allows to cool slowly, observes an initial crystallisation at about 65 ° C, stirs at 20 ° C for 48 hours, isolates the precipitate formed by suctioning, it is washed with ethanol to give 188, 9 g of crude salt between (+) - u-phenylethylamine and "L" -2-isopropyl-2-p-chloro-phenylacetic acid, α + = + 3.5 ° (c = 0.5%, methanol).

DK 171478 B1 6

Cleaning

The 188.9 g crude product is introduced into 4 liters of ethanol with 70% water (by volume) and heated to reflux and ethanol with 70% water (by volume) to obtain complete solution, i.e. 2 liters, which are allowed to cool to 20 ° C, stir for 20 hours at 204 ° C, 5 isolates the precipitate formed by suctioning, washing, drying and obtaining 147.9 g of salt 20 between (+) - α-phenylethylamine and L "-2-Isopropyl-2-p-chlorophenylacetic acid, αβ - + 4.5 ° (c = 0.8%, ethanol), m.p. 210 ° C (dec.).

Step B: Extraction of the mixture of MD "-2-isopropyl-2-p.chlorophenylacetic acid and" D, L "-2-isopropyl-2-p-chlorophenylacetic acid

The mother liquors obtained in step A are evaporated from decomposition and purification to dryness, the residue obtained is suspended in 300 ml of methylene chloride, while stirring, adding 2N hydrochloric acid to one. pH of 1 (about 350 ml of 2N hydrochloric acid), stirs, separates the organic phase by decantation, extracts the aqueous phase with methylene chloride, combines the organic phases, wash them with water, extracts the washing liquids with methylene chloride, dries the organic phase, filters, evaporates to dryness by distillation under reduced pressure to give 153.7 g of a mixture of "D" -2-isopropyl-2-p-chlorophenylacetic acid and "D, L" -2-isopropyl-2- p-chlorphenyled-acid.

20

Step C:

The salt between (-) - α-phenylethylamine and "D" -2-isopropyl-2-p-chlorophenylacetic acid In 4 liters of ethanol with 70% water (by volume) 153 g of mixture of "D" -2-isopropyl-2 are introduced. -p-chlorophenylacetic acid and "D, L" -2-isopropyl-2-p-chlorophenylacetic acid, and to the obtained solution, 86 g of (-) - u -phenylethylamine are added over 15 minutes, the mixture is heated to reflux with stirring , add ethanol with 70% water (by volume) until complete dissolution (2.25 liters), let cool slowly, stir for 20 minutes at 20 ° C, isolate the formed precipitate by suction, wash it with water, dry it and obtain 168.2 g of crude salt between (-) - α-phenylethylamine and "D" -2-isopropyl-2-p-chlorophenylacetic acid, ixQ = -5 ° (c = 0.6%, methanol).

Purification 14 liters of aqueous ethanol solution with 70% water (by volume) introduce 168 g of crude salt between (-) - α-phenylethylamine and "DH-2-isopropyl-2-p-chlorophenylacetic acid, heat the mixture to reflux, add ethanol with 50% water (by volume) until a complete solution (1.5 liters) is allowed to cool to 20 ° C, stirring at 20 ° C for 48 hours, isolates the formed precipitate by suction, washing it with alcohol, drying it and obtained 143.1 g of salt between (-) - u -phenylethylamine and "D" -2-isopropyl-2-p-chlorophenylacetic acid, aD = -5 ° (c = 0.8%, methanol) , mp 210 ° C (decomposition).

Step D: 5 "D" -2-Isopropyl-2-p-chlorophenylacetic acid In 286 ml of methylene chloride 143 g of salt is added between (-) - α-phenylethylamine and "D" -2-iso-propyl-2-p-chlorophenylacetic acid prepared in step C above, adding with stirring 286 ml of 2N hydrochloric acid, stirring for 15 minutes, obtaining two clear phases, separating them by decantation, extracting the aqueous phases with methylene chloride, washing the organic phases with water, extracting the washings with methylene chloride , drying the organic phase, filtering, evaporating to dryness to give 91 g of "D" -2-isopropyl-2-p-chlorophenylacetic acid, αβ = + 42 ° (c = 1%, ethanol), m.p. 105 ° C.

Step E: "D" -2-Isopropyl-2-p-chlorophenylacetic acid chloride In a mixture of 50 ml of petroleum ether (bp 35-70 ° C) and 20 ml of thionyl chloride, 10 g of "D" -2-isopropyl-2 is introduced. -p-chlorophenylacetic acid, heats the mixture to reflux, reflux for 4 hours, cools, evaporates to dryness under reduced pressure and gives 10.8 g of "D" -2-isopropyl-2-p-chlorophenylacetic acid chloride.

Step F:

Esters between (S) -α-cyano-3-phenoxybenzyl alcohol and "D" -2-isopropyl-2-p-chlorophenylacetic acid In 50 ml of benzene 3 g of (S) -α-cyano-3-phenoxybenzyl alcohol are added and 3.1 g of "D" -2-isopropyl-2-p-chlorophenylacetic acid chloride prepared in step E above, cool to 15 ° C, drop dropwise a mixture of 4 ml of pyridine and 10 ml of benzene, stir for 2 hours at 20 ° C, pour in 2N hydrochloric acid, separating the organic phase by decantation, drying, filtering, evaporating to dryness under reduced pressure, chromatographing the residue on silica gel eluting with benzene to give 4.4 g of ester between (S) -acyan -3-phenoxybenzyl alcohol and "D" -2-isopropyl-2-p-chlorophenylacetic acid, and = + 13.5 ° (c = 2%, benzene), which crystallize on standing. Mp.

30 ° C.

Analysis: C25H22CIN O3 = 419.88 C% H% Cl% N% Calcd: 71.50 5.28 8.44 3.34 Found: 71.4 5.3 9.1 3.3 DK 171478 B1 8

Circular dichroism (dioxane): Δε = + 0.1 at 253 nm (max), Δε = +0.23 at 277 nm (max), Δε = +0.27 at 282 nm (max), Δε = +0, 27 at 286 nm (max).

5 N.M.R. Spectrum (Deuterochloroform):

Peaks at 0.63-0.75 ppm; 0.88-1.0 ppm, characteristic of the hydrogen atoms in the methyl groups of isopropyl; peak at 2.25 ppm, characteristic of the hydrogen atom in isopropyl at the carbon atom in α position relative to the asymmetric carbon atom; peak at 3.17-3.33 ppm characteristic of the hydrogen atom at the asymmetric carbon atom of the acid; peak at 6.4 ppm, characteristic of the hydrogen atom at the carbon atom in α position to the nitrile group; peaks at 6.91-7.25, characteristic of the hydrogen atoms in the aromatic rings.

Example 3 (Application Example)

The ester between (S) -α-cyano-3-phenoxybenzyl alcohol and 15 L of R, cis-2,2-dimethyl-3- (2 \ 2'-dibromovinyl) -cyclopropane-1-carboxylic acid

640 mg of (S) -α-cyano-3-phenoxybenzyl alcohol is dissolved in 10 ml of anhydrous toluene, cooled to -10 ° C and 1.25 g of 2,2-dimethyl-3- (2,2,2-dibromovinyl) is slowly added. ) -cyclopropane-1-carboxylic acid chloride in 2 ml of toluene and then 0.5 ml of pyridine in 2 ml of toluene.

The mixture is kept for 2 hours at 20 ° C and then 48 hours at 0 ° C, washed with dilute hydrochloric acid and then with a sodium bicarbonate solution, dried and evaporated to dryness.

2.1 g of the expected product is obtained in crystalline form which is purified by chromatography on silica gel eluting with a mixture of petroleum ether and ether in a ratio of 9: 1. 1.3 g of the expected pure crystalline product are obtained. Mp. 100 ° C, = + 19 ° (c - 0.8%, CHCl 3).

Claims (4)

A process for the preparation of (S) -α-cyano-3-phenoxybenzyl alcohol of formula I CN __k 5Η0-0- / Λ HW / 7 - Λ (l) (s) o - </ \ characterized in that: Reacts (R, S) -α-cyano-3-phenoxybenzyl alcohol in the presence of an acidic agent with the lactone of cis-2,2-dimethyl-3S- (dihydroxymethyl) cyclopropane-1R-carboxylic acid to give a mixture of (1R, 5S) -6,6-dimethyl-4 (R) - ((S) -cyan- (3'-phenoxy-phenyl) -methoxy) -3-oxa-bicyclo (3.1 0.) hexane-2 -one and (1R, 5S) -6,6-dimethyl-4 (R) - ((R) -cyan- (3'-phenoxyphenyl) -methoxy) -3-oxa-bicyclo (3.1.0.) hexane2 -one and separating these two isomers by a physical agent and in an acidic environment hydrolyzes (1R, 5S) -6,6-dimethyl-4 (R) - ((S) -cyan- (3'-phen-15) oxyphenyl) methoxy) -3-oxa-bicyclo (3.1.0) hexan-2-one to give the desired (S) -α-cyano-3-phenoxybenzyl alcohol. Process according to claim 1, characterized in that the acidic agent in the presence of which the alcohol is reacted and the lactonic compound is selected from p-toluenesulfonic acid, 20 methanesulfonic acid, perchloric acid, m-nitrobenzylsulfonic acid, 5-sulfonic salicylic acid and camphosulfonic acid. Process according to claim 1, characterized in that the physical agent is a chromatography on a silica gel column. 25 Process according to claim 1, characterized in that the acid used for the final hydrolysis is p-toluenesulfonic acid. 30